Critique

Alcohol alternatives – a goal for psychopharmacology?

Journal of Psychopharmacology 20(3) (2006) 318–320

D. J. Nutt Psychopharmacology Unit, Bristol University, Bristol, UK.

Drug misuse is the leading preventable cause of excess mortality and morbidity with tobacco being the main mortality culprit as it results in over 100,000 deaths per year in the UK (Foresight, 2005). However alcohol is a growing problem worldwide that some believe may have already overtaken tobacco in terms of overall health and social care costs because of the consequences of intoxication, such as accidents, with subsequent medical complications (Room et al., 2005). Faced with the huge role of tobacco in illness causation, a number of health improvement or harm reduction strategies have been implemented. Initial efforts focused on the reduction of the cancer producing tar content in tobacco and more recently substitute nicotine delivery systems with reduced health consequences such as nicotine gum, patches and lozenges have become readily available. In addition buproprion (Zyban) has been licensed as an aid in smoking cessation where it works possibly by reducing craving or depression during the quit attempt (see Lingford-Hughes et al., 2004). Could similar approaches be used for alcohol? To some extent the drug relapse-prevention approach is already available as both acamprosate and naltrexone have been shown to be helpful in this (see Lingford-Hughes et al., 2004). But could we make a safer alcohol – or a substitute drug alternative? Here we examine the options in the light of the lessons learnt from tobacco.

The toxic element in alcohol is ethanol, a two carbon chain alcohol that has a complex pharmacology (Lingford-Hughes and Nutt, 2003). The sedative, ataxic and eventually terminal anaesthetic actions are thought to be mediated by interactions with primary amino acid ionotropic receptors especially GABA-A and glutamate. Ethanol acts as a GABA-A agonist so increasing central inhibition and as antagonist at the NMDA type of glutamate receptors so reducing central excitation. The pleasurable effects are probably in part due to these interactions but may also involve interactions with endogenous opioids, dopamine and other amine systems. Aspects of alcohol toxicity may reflect specific interactions e.g. the nausea is in part due to agonist actions at the 5HT3 receptor leading to vagal nerve stimulation.

How can these effects be reduced or abolished? One approach is to reduce the concentration of alcohol in drinks. One major reason for the increase in binge intoxication in the UK is the gradual increase in the strength of alcohol in beers and especially lagers. Twenty years ago the average strength of beers and lagers was between 3.5 and 4%. Now it is quite difficult to find such weak drinks on sale in bars as the most popular drinks are in the 5–5.5% range and some strong lagers are up to 8% alcohol. Reducing alcohol concentration would be a simple approach to reducing intoxication and could be done either by law or by taxing according to alcohol content. Some countries e.g. Sweden, already use this approach to alcohol harm reduction by only allowing beers of less than 3.5% alcohol strength to be made available in public places such as airports.

The logical extension of this approach is to remove all alcohol from drinks yet maintain their taste and desirability. Although in practice some set out to get drunk, many drink for other reasons which include, to quench thirst, for the taste and because of the association alcoholic drinks have with other aspects of life such as food and friendship. Of course the psychological effects of alcohol contribute to some of these but in some cases alcohol-free drinks are equally acceptable. Removing alcohol is a practical option for beers/lagers and also some wines although in some cases (especially wine) there is a marked deterioration in taste as well. Greater incentives here could lead to improvements in such drinks so increasing their uptake. Price reductions e.g. through lower taxation could be used to encourage their consumption in relation to intoxicating drinks. There is also scope for legislation to increase uptake – for example it could be made compulsory for all alcohol outlets to have some zero or low alcohol products on sale. Currently it may be difficult to find much choice or even any such drinks in many supermarkets and bars.

What about a safer alcohol? This has been tried in several ways previously using drugs that act in a similar way to alcohol but are free of some of its immediate problematic effects, such as gastric irritation, and do not produce the longer term effects such as cirrhosis, cardiomyopathy and dementia. The first was clomethiazole [Heminevin], a sedative hypnotic drug that was developed as an alternative to the barbiturates for sleep induction but which became used for alcohol withdrawal and other excitable states. Some therapists began to use it to help alcoholics abstain in the community although this soon lost appeal because of the development of dependence on the drug with dose escalation (see Ling-ford-Hughes et al., 2004). However in the absence of any controlled trials it is a moot point whether the harms of clomethiazole were worse than those of the alcohol for which it was being substituted.

Similar considerations apply to the benzodiazepines, which are the current mainstay of withdrawal treatment and have often been used as a form of substitution therapy especially for alcoholics with marked anxiety disorders who have not responded to non-benzodiazepine treatments for their anxiety (see Lingford-Hughes et al., 2004). The third agent – gammahydroxybutytrate (GHB) was not licensed in the UK but has for the past decade been used as an alcohol substitute in Italy on account of its better safety than continued drinking. It is also used as an anaesthetic agent there and in some other European countries. In the UK, GHB has been used off license for its sedative and hormone-releasing properties and because of evidence of harms and abuse was recently controlled under the Misuse of Drugs Act (see Gonzalez and Nutt 2004).

All these three drug alternatives to alcohol have been criticised because dependence may develop to the drugs themselves and they may be abused and sold. Also drinking alcohol on top of each of them can lead to excessive sedation and intoxication and potentially terminal coma. They therefore have had limited use as treatment alternatives despite their safety benefits over alcohol. However modern pharmacology may offer a more interesting future if these problems could be engineered out of a molecule. Some might argue that if a substitute drug is to be viable it has to so like alcohol as to be inevitably abused. However experience in the opiate field suggests this is not the case as buprenorphine, a partial agonist at the mu receptor is highly effective as a substitute agent despite having much lower efficacy than heroin (Law et al., 2004). The last decade has seen huge advances in our understanding of the GABA-A benzodiazepine receptor (Nutt and Malizia, 2001) and partial agonists (PA) of various degrees have been synthesized and some tested in humans as potential anxiolytics (Potokar and Nutt, 1994). Many of these show little or no interactions with alcohol so the risk from combined use would be low. They also show little sedation even in overdose and few signs of dependence or withdrawal in animals are reported. Moreover they seem to have low to zero abuse propensity and have the additional safety benefit over alcohol that an overdose can be instantly reversed by administering an antagonist e.g. flumazenil.

The future offers even greater potential if the emerging understanding of the differential functions of the various GABA-A receptor subtypes leads to the development of subtype-selective PAs (Nutt, 2005). Evidence is just beginning to emerge that different actions of alcohol are mediated via different subtypes e.g. the amnestic actions seem to depend on the α5 subtype probably in the hippocampus (Wilson et al., 2005), and some of the reinforcing effects might be via the α4δsubtype (Sundstrom-Poromaa et al., 2002) . This understanding will in theory allow new compounds to be made that do not bind to certain receptors, so removing these actions from their profile. In other words it might be possible to make a PA that did not bind to the α5 receptor subtype so would not impair memory. If the subtype responsible for the aggression-promoting actions of alcohol could be identified then binding to this could be eliminated. Similarly it might be possible to develop a PA that was pleasurable but did not cause dyscordination or sedation, so might allow driving after consumption. One could even envisage the situation where, after a party where PAs were consumed, the revellers took an antagonist such as a longer acting flumazenil so allowing them to ‘sober-up’ instantly and be able to drive home quite safely.

Glutamate receptors offer potential new drug targets for alternatives to alcohol though with less certainty than the GABA - A system at present as so few glutamatergic drugs have been studied in humans. However one could envisage that an NMDA antagonist might be somewhat alcohol-like and although it would probably impair memory like alcohol it could still be safer than alcohol in many other aspects, though reversal with an antagonist would not be possible. Another approach involves the development of drugs that act at G-protein coupled glutamate receptors (metabotropic receptors) where some compounds with anxiolytic potential have already been identified (Swanson et al., 2005).

One important consideration is the pharmacokinetic question of how best to deliver a safer alcohol. The standard way alcohol is consumed is by drinking, usually over a few hours, though people with severe dependence may down a litre of spirits in minutes. In the case of beers/lagers alcohol is provided as relatively dilute solution, wines are stronger and spirits the maximum concentration that can be obtained by simple distillation. Benzodiazepine GABA-A receptor PAs or other alcohol alternatives might need to be available in different strengths to mirror this. Part of the pleasure of alcohol – at least for the non-dependent drinker – is the taste and the associated rituals of consumption that may fill primitive appetitive functions. It seems likely that providing alcohol alternatives in a drinkable form would be important in their gaining acceptance. Moreover drinking allows the titration of input in a way that taking a pill does not. Ideally an alcohol alternative would have similar absorption and brain entry kinetics to alcohol so that experienced alcohol users could most easily switch to the new drug. In practice this may not be too difficult.

Could these pharmacological alternatives to alcohol become a reality? In some countries, bars that offer oxygen in different flavours have been opened, so could we have PA bars as well? Current UK legislation makes this difficult, as the drug alternatives would have to be licensed under the Medicines Act and prescribed by doctors whereas alcohol is controlled as a foodstuff/commodity. The recent OST Foresight programme, Brain Science Addiction and Drugs (Foresight, 2005) has pointed out this dilemma. One possibility would be to license a PA as a general sales list medication so allowing purchase in retail outlets such as supermarkets. But even though this is possible under current law it would be hard to envisage the indication of alcohol-like pleasure being accepted in the current regulatory climate even if the safety benefits vis-à-vis alcohol were profound. Perhaps the Foresight report will encourage some ambitious pharma companies to take up this challenge and try to make a safer alcohol, and use this to challenge the current regulatory barriers. The benefits to society could be so profound that legislative change might be readily produced!